ABSTRACT The objective of this proposal is to explore the use of novel NO releasing sensor membranes for developing improved subcutaneous glucose biosensors that function more reliably in vivo. The concept of using local NO release to enhance the performance of in vivo subcutaneous sensors represents a novel approach that may overcome the key obstacles that have prevented the development of in vivo biosensors that function reliably once implanted in patients. Current scientific knowledge regarding the role of NO in angiogenesis, phagocytosis, thrombosis, and wound healing suggests that the controlled release of NO at a sensor interface may increase blood flow to the sensor, reduce inflammation, and promote wound healing by inhibiting bacterial adhesion and minimizing the thickness of the ensuing capsule. Favorable biocompatibility thus may minimize host physiological responses such that the in vivo performance of current subcutaneous biosensors would be dramatically improved. Following the synthesis of NO-releasing sensor membranes with adequate analyte permeability and a wide range of NO release characteristics including flux and duration, we will: 1) evaluate the tissue biocompatibility of such materials in vivo as a function of NO release properties;2) fabricate functional NO-releasing glucose microsensors;3) evaluate the in vivo analytical performance of such sensors in a pig model. The proposed research has the potential to lead to implantable glucose sensors that exhibit reduced biofouling and bacterial infection, enhanced wound healing, and improved analytical performance. A functional glucose sensor with these characteristics would impact millions of diabetic patients who are potential candidates for continuous glucose monitoring devices. PROJECT NARRATIVE The objective of this proposal is to explore the use of novel nitric oxide (NO)-releasing sensor membranes for developing improved subcutaneous glucose biosensors that function more reliably in vivo. The proposed research has the potential to lead to implantable glucose sensors that exhibit reduced biofouling and bacterial infection, enhanced wound healing, and improved analytical performance.